Esters of 17alpha-alkynylester-5(10)-ene-3beta, 17beta-diols



United States Patent 3,092,645 ESTERS 0F 17a-ALKYNYLES'I'ER-S(1fi)-ENE-3fl,ll7fl-DZQLS Robert T. Nicholson, Glenview, llL, assignor to G. D.Searle & Co, Chicago, 111., a corporation of Delaware No Drawing. FiledDec. 28, 1961, Ser. No. 162,917 3 Claims. (Ci. 250-6975) The presentinvention is concerned with diesters of steroidal diols and, moreparticularly, with esters of 17aalkynylestr-5(10)-ene-3B,l7fi-diols,which can be represented by the structural formula wherein R and R arelower alkyl radicals and X is a lower alkynyl radical.

The lower alkyl radicals encompassed by the R and R terms are,typically, methyl, ethyl, propyl, butyl, pentyl, hexyl, and thebranched-chain isomers thereof. Examples of lower alkynyl radicals areethyny-l, propynyl, butynyl, pentynyl, hexynyl, and the branched-chainradicals isomeric therewith.

Starting materials suitable for the manufacture of the compounds of thisinvention are the l7aalkynylestr- 5(10)-ene-35,17/3-diols of thestructural formula wherein X is a lower alkynyl radical. These materialscan be obtained by reaction of the corresponding17aalkynyl-17B-hydroxyestr-5(10)-en-3-ones with a suitable reducingagent. A preferred reagent is lithium hi-(tertiary-butoxy) aluminumhydride, although other reducing agents such as sodium borohydride,potassium borohydride, and lithium aluminum hydride can also be used.This process is typified by the reaction of l7a-ethynyl-17B-hydroxyester-5 (10)-en-3-one in tetrahydrofuran with lithiumtri-(tentiary-butoxy) aluminum hydride to afiord 17a-ethynylestr-5 10)-ene-3 13,17/8-diol.

Reaction of the latter diols with a suitable acylating agent affords thediesters of this invention. Typically, the aforementioned17a-ethynylestr-5(10)-ene-3,8,17,8- diol is treated, for example, withacetic 'anhydride and pyridine at the reflux temperature to producel7a-ethynylestr-S (l0) -ene-3 3,17,9-diol 3,17-diacetate.

The compounds of this invention exhibit valuable pharmacologicalproperties. They are, for example, estrogenic agents which lack theprogestational proliferating side-effect on the endometrial gland.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only, and it will beunderstood that EfihZfiS Patented June 4, i963 Example 1 To a solutionof 130.9 parts of lithium tri(tertiarybutoxy) aluminum hydride in 314parts of tetrahydrofuran is added dropwise, at 05, in a nitrogenatmosphere, a solution of 35 pants of l7a-ethynyl-17 3hydroxyestr-5(10)-en-3-one in 373 parts of tetrahydrofuran. This mixture is stirred atroom temperature for about 3 /2 hours, then is cooled to 05 andacidified to pH 24 by the addition of 10% sulfuric acid. The supernatantliquid phase is decanted from the precipitated salts, then is dilutedwith water. The crystalline product which forms is collected byfiltration and dried to yield 17u-ethyny-lestr- 5(l0)-ene-3/3,17B-diol,Ml. about -141. Recrystallization from methanol affords a pure samplemelting at about 137-139.

Example 2 A mixture of 10 parts of l7wethynylestr-5(10)-cue3,9,17fi-diol, 54 parts of acetic anhydride, and 98 parts of pyridine isheated at reflux, under nitrogen, for about 2 /2 hours, then is cooled,diluted with ice and water, and extracted with ethyl acetate. Theorganic extract is washed with water, dried over anhydrous sodiumsulfate, and concentrated to dryness in vacuo. The partially crystallineresidue is recrystallized from methanol to produce17o:-ethynylestr-5(l0)-ene-3,8,l7f3-diol 3,17-diacetate, MP. about127-129"; [0c] =+-87 (chloroform). This compound exhibits characteristicinfrared maxima at about 3.03, 5.72, and 8.00-8.12 microns.

Example 3 A mixture of one part of 17a-ethynylestr-5(10)-ene- 36,17/3-diol, 5 parts of propionic anhydride, and 9.8 parts of pyridineis heated at reflux, under nitrogen, for about 2 /2 hours. This reactionmixture is then cooled, diluted with ice and water, and extracted withethyl acetate. The organic extract is Washed with Water, dried overanhydrous sodium sulfate, and concentrated to dryness at reducedpressure to afford pure 17u-ethynylestr-5(l0) -ene 35,17,8-diol3,17-dipropionate, obtained as an oil. It is characterized by infraredmaxima at about 3.00, 5.75, and 8.12-8.30 microns.

What is claimed is:

1. A compound of the formula ii OCR i RCO 3,17-diace- No referencescited.

1. A COMPOUND OF THE FORMULA